The diagnosis of diastolic congestive heart failure (CHF) can be made when patients have symptoms and signs of fluid overload, a normal ejection fraction, and pronounced abnormalities in diastolic function. In a general population of patients with CHF, the prevalence of diastolic CHF is 30-35% and the 5 year mortality rate is 25%. In patients over 70 years old, the prevalence of diastolic CHF increases to 50% and the 5 year mortality rate approaches 50%. Therefore, diastolic CHF is a major health care problem, especially in our aging population. Despite its importance, the basic underlying mechanisms that cause diastolic CHF and the impact that aging makes on these mechanisms are not completely understood. For these reasons, the primary focus of my research has been to define the mechanisms, which cause abnormal diastolic function. Diastolic CHF develops when there has been a fundamental alteration in the passive material properties of the cardiac muscle tissue (i.e., increased diastolic myocardial stiffness). Three of the possible mechanisms which may cause this increase in myocardial stiffness include changes in the cardiac muscle cell (cardiocyte), changes in the extracellular matrix (ECM), and changes in neurohumoral activation. I believe that changes in each of these three mechanisms, individually and in combination, cause the abnormalities in diastolic function that lead to diastolic CHF. Studies examining the ECM and neurohumoral activation are the subject of my ongoing Department of Veterans Affairs Merit Review grant. Studies examining mechanisms within the cardiocyte will be the focus of this Program Project Proposal. The purpose of Project 6 is to prove the hypothesis that basic cardiocyte mechanisms play a significant cause and effect role in the development of the diastolic CHF. This hypothesis will be tested using three specific aims: 1) Determine whether, and to what degree, changes in the viscoelastic properties of the cardiocyte occur in, and are causally related to the increased myocardial stiffness produced by pressure-overload hypertrophy (POH) and advanced age, 2) Define the basic cellular mechanisms which cause increased cardiocyte viscoelastic stiffness, and 3) Determine whether transgenic modulation of these basic cellular mechanisms will prevent or correct the increases in diastolic stiffness produced by POH and advanced age.